ABSTRACT. Retinal neovascular diseases including neovascular age-related macular degeneration, diabetic macular edema and retinal vein occlusion are the most vision-threatening diseases among the working-age population in the developed world. Therapies targeting vascular endothelial growth factor (VEGF) delay the development of neovascularization in some but not all patients, implicating additional factor(s) in retinal neovascular pathogenesis. In addition, these therapies require frequent intraocular injections representing a significant burden for both patients and physicians and entail a small risk of endophthalmitis, uveitis, vitreous hemorrhage and other complications. Thus, there is much needed a retinal neovascular disease treatment that can be delivered less frequently and yet provide the same or better vision protection than current anti-VEGF therapies. Abzyme Therapeutics LLC recently has isolated several potent single domain modular antibodies against VEGF and CD147, the latter being a potent angiogenic factor and an inducer of matrix metalloproteinase synthesis and also reported to be present at high levels in the vitreous humor of retinal neovascular patients. Using these antibodies in combination with a single domain antibody that binds to hyaluronan, a major macromolecular component of the eye's vitreous compartment, we propose to develop a novel long-acting multi-specific antibody capable of simultaneously inhibiting both VEGF and CD147 for retinal neovascular disease treatment. In Phase I, a panel of multi-specific antibodies will be produced, and their anti-angiogenic inhibition activity will be validated. In Phase II, the anti-neovascularization activity and in vivo half-life of selected antibody drug candidates will be characterized, validated in animal models and humanized in preparation for IND submission.